15 September 2010

EMA/HMPC/96910/2010
Committee on Herbal Medicinal Products (HMPC)

Assessment report on Commiphora molmol Engler,

gummi-resina
Based on Article 16d(1), Article 16f and Article 16h of Directive 2001/83/EC as amended (traditional
use)

Draft

Herbal substance(s) (binomial scientific name of

the plant, including plant part) Commiphora molmol Engler, gummi-resina

Herbal preparation(s) Tincture (ratio of herbal substance to extraction

solvent 1:5), extraction solvent ethanol 90 %
(V/V)

Pharmaceutical forms Liquid dosage forms for oromucosal or cutaneous

use

Rapporteur

Assessor(s)

Note: This draft Assessment Report is published to support the release for public consultation of the
draft Community herbal monograph on Commiphora molmol Engler, gummi-resina. It should be noted
that this document is a working document, not yet fully edited, and which shall be further developed
after the release for consultation of the monograph. Interested parties are welcome to submit
comments to the HMPC secretariat, which the Rapporteur and the MLWP will take into consideration
but no overview of comments received during the public consultation will be prepared in relation to
the comments that will be received on this assessment report. The publication of this draft assessment
report has been agreed to facilitate the understanding by Interested Parties of the assessment that has
been carried out so far and led to the preparation of the draft monograph.

7 Westferry Circus Canary Wharf London E14 4HB United Kingdom

Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7051
E-mail info@ema.europa.eu Website www.ema.europa.eu An agency of the European Union

European Medicines Agency, 2010. Reproduction is authorised provided the source is acknowledged.
Table of contents
Table of contents ................................................................................................................... 2

1. Introduction....................................................................................................................... 3
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof . 3
Information about products on the market in the Member States.................................... 3
1.3. Search and assessment methodology.................................................................... 5
2. Historical data on medicinal use ........................................................................................ 5
2.1. Information on period of medicinal use in the Community ........................................ 5
2.2. Information on traditional/current indications and specified substances/preparations ... 5
2.3. Specified strength/posology/route of administration/duration of use for relevant
preparations and indications....................................................................................... 5
Non-Clinical Data .................................................................................................................. 6

3. ........................................................................................................................................... 6
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ........................................................... 6
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal
preparation(s) and relevant constituents thereof ......................................................... 11
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal
preparation(s) and constituents thereof ..................................................................... 11
3.4. Overall conclusions on non-clinical data ............................................................... 12
4. Clinical Data ..................................................................................................................... 12
4.1. Clinical Pharmacology ....................................................................................... 12
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ...................................................................... 12
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s)
including data on relevant constituents ...................................................................... 12
4.2. Clinical Efficacy ................................................................................................ 13
4.2.1. Dose response studies.................................................................................... 13
4.2.2. Clinical studies (case studies and clinical trials).................................................. 13
4.2.3. Clinical studies in special populations (e.g. elderly and children)........................... 13
4.3. Overall conclusions on clinical pharmacology and efficacy ...................................... 13
5. Clinical Safety/Pharmacovigilance ................................................................................... 14
5.1. Overview of toxicological/safety data from clinical trials in humans.......................... 14
5.2. Patient exposure .............................................................................................. 14
5.3. Adverse events and serious adverse events and deaths ......................................... 14
5.4. Laboratory findings .......................................................................................... 14
5.5. Safety in special populations and situations ......................................................... 14
5.6. Overall conclusions on clinical safety ................................................................... 14
6. Overall conclusions .......................................................................................................... 15

Annex .................................................................................................................................. 16

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1. Introduction

1.1. Description of the herbal substance(s), herbal preparation(s) or

combinations thereof

Herbal substance(s)

Gumresin, hardened in air, obtained by incision or produced by spontaneous exudation from the stem
and branches of Commiphora molmol Engler and/or other species of Commiphora, complying with the
monograph of the European Pharmacopoeia (01/2008:1349).

Commiphora myrrha (Nees) Engler is a synonym of Commiphora molmol Engler. Other species which
may be acceptable as sources of myrrh are Commiphora abyssinica (Berg) Engler and Commiphora
schimperi (Berg) Engler (ESCOP 2003).

Herbal preparation(s)

Myrrh tincture (1:5; extraction solvent: ethanol 90% V/V), Ph. Eur. monograph (01/2008:1877).

Combinations of herbal substance(s) and/or herbal preparation(s) including a description of

vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products
assessed, where applicable.

1.2. Information about products on the market in the Member States

According to the information provided by the National Competent Authorities:

Austria: Myrrh is present in combination products (as ethanolic extracts) used as bitters for stomach
problems. Myrrh tincture (apparently pharmacy made) is used in phytotherapy for inflammations of the
gingiva.

Czech Republic: No single active ingredient products available, but several combination products
(Schwedenbitter) containing myrrh, used as adjuvants in mild gastrointestinal complaints, are
available.

Denmark: Some MAs (from 1980) containing myrrh tincture, either alone or in combination products.
Used as local astringent and anaesthetic in the mouth.

Estonia: One combination product registered.

Germany: Myrrh tincture (1:5; extraction solvent: ethanol 90% v/v), and a dry extract (4-6:1;
extraction solvent ethanol 60% m/m) available in combination products. Myrrh tincture as single active
ingredient is available as a product with a German standard marketing authorisation.

Slovenia: No single active ingredient products available, but several combination products
(Schwedenbitter) containing myrrh, used as adjuvants in mild gastrointestinal complaints, are
available.

United Kingdom: Myrrh tincture (BPC) is available as a product first approved in 1972. The indications
are: 1) Ulcers in the mouth and pharynx; 5 ml directly applied as required or diluted with water to 20
ml and used as a gargle as required - 2) Flatulence; 2.5-5 ml 3 times daily as required. The product is
not recommended for children under 12 years of age.

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Regulatory status overview

Member State Regulatory Status Comments (not

mandatory field)

Austria MA TRAD Other TRAD Other Specify: Combination products

Belgium MA TRAD Other TRAD Other Specify: No products
Bulgaria MA TRAD Other TRAD Other Specify:
Cyprus MA TRAD Other TRAD Other Specify:
Czech Republic MA TRAD Other TRAD Other Specify: Combination products
Denmark MA TRAD Other TRAD Other Specify:
Estonia MA TRAD Other TRAD Other Specify: Combination products
Finland MA TRAD Other TRAD Other Specify: No products
France MA TRAD Other TRAD Other Specify:
Germany MA TRAD Other TRAD Other Specify:
Greece MA TRAD Other TRAD Other Specify:
Hungary MA TRAD Other TRAD Other Specify:
Iceland MA TRAD Other TRAD Other Specify:
Ireland MA TRAD Other TRAD Other Specify:
Italy MA TRAD Other TRAD Other Specify: No products
Latvia MA TRAD Other TRAD Other Specify:
Liechtenstein MA TRAD Other TRAD Other Specify:
Lithuania MA TRAD Other TRAD Other Specify:
Luxemburg MA TRAD Other TRAD Other Specify:
Malta MA TRAD Other TRAD Other Specify:
The Netherlands MA TRAD Other TRAD Other Specify: No products
Norway MA TRAD Other TRAD Other Specify: No products
Poland MA TRAD Other TRAD Other Specify: No products
Portugal MA TRAD Other TRAD Other Specify:
Romania MA TRAD Other TRAD Other Specify:
Slovak Republic MA TRAD Other TRAD Other Specify: No products
Slovenia MA TRAD Other TRAD Other Specify: Combination product
Spain MA TRAD Other TRAD Other Specify: No products
Sweden MA TRAD Other TRAD Other Specify: No products
United Kingdom MA TRAD Other TRAD Other Specify:
MA: Marketing Authorisation
TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration
Other: If known, it should be specified or otherwise add Not Known
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the
products in the MSs concerned.

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1.3. Search and assessment methodology

PubMed was searched on 27 January 2010 using the terms [myrrh OR commiphora molmol OR
commiphora mol mol OR commiphora myrrha]. 122 references were retrieved. The abstracts were
screened manually and all articles deemed relevant were assessed and included in the list of
references.

2. Historical data on medicinal use

Myrrh appears to be one of the oldest medicines. Its use was recorded in the recipes from ancient
Rome and in the texts of Hippocrates. Myrrh is also mentioned in both the Bible and the Koran
(Madaus 1938).

2.1. Information on period of medicinal use in the Community

Myrrh has been used within the European Union for more than 30 years (Braun 1968, Madaus 1938,
Moritz 1967). The herbal preparation mainly used seems to be the tincture (Ph. Eur. 2008, ESCOP
2003, Kommission E 1987, Bradley 1992, Todd 1967, Barnes 2007).

2.2. Information on traditional/current indications and specified

substances/preparations

The current use of myrrh in the form of tincture (1:5, extraction solvent ethanol 90% V/V) for
oromucosal treatment of minor ulcers and inflammation in the mouth (stomatitis and gingivitis) is well-
documented in recent handbooks (e.g. ESCOP 2003, Bradley 1992, Blumenthal 2000, Barnes 2007).
The use of undiluted myrrh tincture to paint the affected areas in the mouth is also well-documented
(Blumenthal 2000, Hnsel 1992, Information from UK).

Another current use of myrrh tincture is the topical application to minor wounds, abrasions, furuncles
and skin inflammations (Barnes 2007, ESCOP 2003, Hnsel 1992, Bradley 1992).

Historically, myrrh (tincture) has had a medicinal use to relieve various gastrointestinal disorders, such
as indigestion and intestinal infections (Todd 1967, Hnsel 1992, Bradley 1992, Information from UK,
Madaus 1938), but this use seems to have declined (Hnsel 1992, Bradley 1992, ESCOP 2003, Barnes
2007). The oral use of myrrh tincture in combination products is still in practice within the Member
States (Information from e.g. Austria, Czech Republic, Denmark, Estonia, Germany, Slovenia, UK).

2.3. Specified strength/posology/route of administration/duration of use

for relevant preparations and indications

Recommended posology for oromucosal use of myrrh tincture (1 g = 65 drops; 0.8194 g/ml; 0.02
ml/drop) as a gargle:
30-60 drops (0.6-1.2 ml) of tincture in a glass of warm water (Blumenthal 2000).

5 ml of tincture in a glass of water 3 times daily (Bradley 1992).

5 ml of tincture in 15 ml of water (Information from UK).

1-5 ml of tincture in a glass of water several times daily (ESCOP 2003).

20-30 drops (0.4-0.6 ml) of tincture in a glass of water several times daily (Madaus 1938).

2.5-5 ml in a glass of water several times daily (Barnes 2007).

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Based on this information, the following posology appears well founded in European tradition:

0.5-5 ml of myrrh tincture in a glass of water 3 times daily.

Recommended posology for direct oromucosal application of myrrh tincture:

Apply the undiluted tincture to the affected areas on the gums or the mucous membranes of the
mouth. Paint with a brush or swab, 2-3 times daily (Blumenthal 2000).

Paint the affected areas 2-3 daily with undiluted tincture (Hnsel 1992).

Apply undiluted tincture directly as required (information from UK).

Recommended posology for topical use of myrrh tincture on the skin:

Apply undiluted tincture (Bradley 1992).

For use on skin, dab 2-3 times daily with diluted or undiluted tincture (ESCOP 2003).

For skin, diluted or undiluted (Barnes 2007).

3. Non-Clinical Data

3.1. Overview of available pharmacological data regarding the herbal

substance(s), herbal preparation(s) and relevant constituents thereof

Constituents:

Volatile oil, resin and gum. The main constituents of the volatile oil are furano-sesquiterpenes with
furanodesma-1.3-diene as the main component (structure: see below). Important components of the
resin are -, - and -commiphoric acids, - and -heerabomyrrhols, heeraboresene, commiferin,
burseracin, various terpenes. Also present are the steroids campesterol, cholesterol and -sitosterol
(ESCOP 2003, Hagers Handbuch 1992, Wichtl 1989).

O O O

Furanodesma-1,3-diene Curzarene Furanodiene

O
O
O

O
Furanodiene-6-one
Methoxyfuranoguaia-9-ene-8one

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Isolation of furano-sesquiterpenes not mentioned in the above cited handbooks is described by
Maradufu (1982, 1988).
A review of myrrh, including products from other Commiphora species than the ones accepted as
sources of myrrh, is published by El Ashry (2003).
The sesquiterpenes furanodesma-1.3-diene, curzarene, furanodiene, furanodiene-6-one and
metyhoxyfuranoguaia-9-ene-8-one have been found to have antibacterial, antifungal, analgesic and
local anaesthetic effects, see pharmacological effects below (Dolara 1996a, 1996b and 2000).
Two new furano-sesquiterpenes were isolated from Commiphora myrrha Engl. (= C. molmol (Nees)
Engl.) and their structures determined (Zhu 2001).
Six aromatic sesquiterpenes were isolated from Commiphora myrrha Engl. One was a new furano-
sesquiterpene and one was identified as a new natural aroma previously not found in the genus
Commiphora. The others were isolated for the first time from Commiphora myrrha Engl. (Zhu 2003).
The sesquiterpenes cadina-3-en-15-ol (myrracadinol A),7,8-seco-2,5-dihydroxy-12-acetoxycalam-8-
ene (myrracalamene A), 7,8-seco-2,3,5-hydroxy-12-acetoxycalame-8-ene (myrracalamene B), 7,8-
seco-cadin-3,8-dien-2,12-diol (myrracadinol B), 7,8-seco-12-hydroxycalam-8-ene (myrracalamene
C), 7, 8-seco-cadin-3,7(12)-dien-5,10-diol (myrracadinol C) along with a known compound triacont-
1-ene were isolated from Commiphora myrrha (Nees) Engl. and their structures elucidated on the basis
of spectral and chemical analyses (Ahmed 2006).
The octanordammaranes mansumbinone and 3.4-seco-mansumbinoic acid as well as the
sesquiterpenes -elemene and T-cadinol were isolated from the oleo-resin of Commiphora molmol
Engl. (Rahman 2008).
A review of the constituents found in myrrh and frankincense has been published by Shen (2008).
The watersoluble gum fraction of myrrh (40% w/w) has been found to comprise a mixture of
proteoglycans with dominating amounts of uronic acid rich polymers (Wiendl 1995).

Pharmacological effects relevant to traditional use:

Antibacterial and antifungal effects

A fraction from an n-hexane extract of myrrh containing a mixture of furanodiene-6-one and
methoxyfuranoguaia-9-ene-8-one had antibacterial effect against Pseudomonas aeruginosa,
Staphylococcus aureus and Escherichia coli as well as antifungal effect against Candida albicans with
minimum inhibitory concentrations of 0.18 2.8 g/ml (Dolara 2000).
The crude chloroform extract of the oleo-resin of C. molmol displayed potentiation of ciprofloxacin and
tetracycline against S. aureus, several Salmonella enterica strains and two K. pneumoniae strains. The
antibacterial activity of the terpenes mansumbinone, 3.4-seco-mansumbinoic acid, -elemene and T-
cadinol was determined against a number of Staphylococcus aureus strains: SA1199B, ATCC25923,
XU212, RN4220 and EMRSA15 and minimum inhibitory concentration (MIC) values were found to be in
the range of 4-256 g/ml. The highest activity was observed by 3.4-seco-mansumbinoic acid with an
MIC of 4 g/ml against SA1199B, a multidrug-resistant strain which over-expresses the NorA efflux
transporter, the major characterized antibiotic pump in this species. This activity compared favorably
to the antibiotic norfloxacin with an MIC of 32 g/ml. This compound also displayed weak potentiation
of ciprofloxacin and tetracycline activity against strains of Salmonella enterica serovar Typhimurium
SL1344 and L10 (Rahman 2008).

Assessors comments: Myrrh contains terpenes with fairly potent antibacterial effect against several
bacteria including the most common wound pathogen S. aureus. The antibacterial effect has been
shown in vitro and the mechanism of action is not known.

Local anaesthetic activity

A fraction from myrrh containing a mixture of furanodiene-6-one and methoxyfuranoguaia-9-ene-8-
one, in approximately equivalent amounts, had local anaesthetic activity (p<0.01) when administered

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in eye drops (2% DMSO + phosphate buffer) at a concentration of 280 g/ml in the conjunctival sac of
male New Zealand albino rabbits. The vehicle was used as control. The effect was about half that of
procain at 100 g/ml. The local anaesthetic effect of the terpene mixture was shown to be due to
inhibition of sodium inward currents in excitable mammalian membranes (Dolara 2000).

Assessors comments: Myrrh contains terpenes exhibiting local anaesthetic activity in animal
experiments.

Anti-inflammatory effects
An ethanol extract of the oleo-gum resin of Commiphora molmol in an i.p. dose of 400 mg/kg reduced
the weight of xylene-induced ear oedema in mice with 50 53% (p<0.05). In rats, an oral dose of 400
mg/kg significantly (p<0.05) reduced the weight of cotton pellet granuloma (Atta 1998).

In rats, the petroleum ether extract of the oleo-gum resin of Commiphora molmol produced significant
inhibition of carrageenan induced inflammation and cotton pellet granuloma in rats at an oral dose of
500 mg/kg bw (Tariq 1985).

Assessors comments: The oral doses required for anti-inflammatory activity are comparatively high.
No information is available concerning possible anti-inflammatory effects following topical application.

Analgesic effects
In mice, a suspension of ground myrrh in saline at an oral dose of 1 g/kg significantly (p<0.01)
increased the latency of pain reaction (paw licking) when placed on a 52C metal plate. The
sesquiterpenes furanoeudesma-1.3-diene and curzarene, isolated from myrrh, were found to be
analgesic to mice in this test at an intracerebro-ventricular dose of 1.25 mg/kg, whereas a third
sesquiterpene furanodiene was ineffective. Furanoeudesma-1.3-diene, at an oral dose of 50
mg/kg, had the same effect. This oral dose also considerably reduced the number of writhes in mice
after i.p. administration of 0.6% acetic acid. This effect was completely reversed by naloxone.
Furanoeudesma-1.3-diene displaced concentration-dependently the specific binding of the opioid 3H-
diprenorphine to brain membranes (Dolara 1996a, 1996b).
Administered orally to mice, an ethanol extract of myrrh had a significant and dose-dependent
analgesic effect in the acetic-acid writhing test at 200 mg/kg (p<0.05) and 400 mg/kg (p<0.01) (Atta
1998).

Assessors comments: In high doses, orally administered myrrh and isolated terpenes have an
analgesic effect in animal experiments. The effect can be blocked with naloxone, which indicates an
interaction with brain opioid mechanisms.

Other reported pharmacological effects:

Antipyretic effect
After oral administration to hyperetic mice of either an ethanolic or a petroleum ether extract of myrrh
(25:1) at a dose of 500 mg/kg body weight, a significant antipyretic effect (p<0.001) was
demonstrated (Mohsin 1989, Tariq 1985).

Stimulation of phagocytosis
Mice inoculated with Escherichia coli were treated intraperitoneally with either a dried ethanolic extract
or the unsaponifiable fraction of myrrh, as solutions in aqueous ethanol (10% V/V) at 50 mg/kg (1 mg
per 20 g animal). Both treatments stimulated phagocytosis in over 80% of the mice compared to
controls (Delaveau 1980).

Cytoprotective effect
Oral administration of myrrh to rats at 250, 500 and 1000 mg/kg body weight provided significant and
dose-dependent protection to the gastric mucosa against the ulcerogenic effects of various necrotizing

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agents: 80% ethanol, 25% sodium chloride, 0.2 M sodium hydroxide, indometacin 30 mg/kg and
combined ethanol 80%-indometacin 2.5 mg/kg (p<0.05 to p<0.001, depending on the dose). The
same suspension significantly and dose-dependently protected against ethanol-induced depletion of
gastric wall mucus (p<0.05 at 500 mg/kg; p<0.001 at 1000 mg/kg) (Al-Harbi 1997).

Protective effect against liver oxidative damage and genotoxicity

The effect of lead acetate in the diet (0.5% w/w) on reduced GSH, activity on phase II metabolizing
enzyme glutathione S-transferase (GST), lipid peroxidation in liver homogenate and bone marrow
chromosomes of mice, simultaneously supplemented with 1% myrrh powder for 8 weeks was
investigated. Compared with negative control (only diet), GSH decreased in both positive control (diet
+ lead acetate) and treated group (diet + lead acetate + myrrh). GST decreased in positive control but
increased in the treated group compared to both negative and positive control. Lipid peroxidation was
reduced by 45% in the treated group compared to both positive and negative control. Lead
genotoxicity was confirmed through significant reduction in the number of dividing cells, increased total
number of aberrant cells and increased frequency of chromosomal aberrations. The genotoxicity was
significantly reduced by treatment with myrrh (El-Ashmawy 2006).

Antitumour and cytotoxic effects

The anticarcinogenic potential of Commiphora molmol (oleoresin) was studied in Ehrlich-solid-tumor-
bearing mice. Treatment with C. molmol (250 and 500 mg/kg/day) was found to be cytotoxic in Ehrlich
solid tumors cells. The antitumor potential of C. molmol was comparable to the standard cytotoxic drug
cyclophosphamide. This effect of C. molmol was less pronounced after 50 days of treatment (Al-Harbi
1994).

Oral doses of 125, 250 and 500 mg of an aqueous suspension of myrrh given to mice for 7 days had
no effect on the incidence of micronucleated polychromatic erythrocytes (PCE) in the bone marrow but
in comparison to the control groups there was a statistically significant decrease in the PCE/NCE ratio
(NCE = normochromatic erythrocytes), indicating the cytotoxic potential of myrrh, which was found to
be comparable to that of cyclophosphamide. The levels of DNA and protein in hepatic cells were not
affected by treatment with myrrh but there was a significant decrease in their RNA content,
comparable to that caused by cyclophosphamide. In Ehrlich ascites carcinoma (EAC) cell-bearing mice
oral doses of 500 mg/kg of the myrrh suspension caused significant reductions in the DNA (p<0.05),
RNA (p<0.01) and protein (p<0.01) contents of the EAC cells and in their viability (p<0.05). An
increased survival rate of the animals was also observed (Qureshi 1993).

The furano-sesquiterpenoid rel-1S,2S-epoxy-4R-furanogermacr-10(15)-en-6-one exhibited weak

cytotoxic activity against a MCF-7- breast tumor cell line in a clonogenic assay (Zhu 2001).

Effects in gingival cells

Through their production of cytokines such as IL-6 and IL-8, human gingival fibroblasts and epithelial
cells act as accessory immune cells, thereby contributing to peridontal destruction. The cytotoxicity of
the essential oil from myrrh (Commiphora molmol) (MO) to human gingival fibroblasts and epithelial
cells and the effect on interleukin (IL)-1-stimulated production of IL-6 and IL-8 has been determined.
Cell viability and cytotoxicity were determined by metabolic reduction of a tetrazolium salt to a
formazan dye (MTT assay) and by release of lactate dehydrogenase (LDH) from membrane damaged
(LDH release assay) cells, respectively. Based on the MTT assay, 24- and 48-h exposures to 0.001%
MO had little effect on fibroblast and epithelial cell (24-h only) viability. At 48 h, 0.0005-0.001% MO
decreased epithelial cell viability 30-50%. After 24 and 48 h, MO, at 0.005%, maximally decreased
viability of all cell lines. In the LDH release assay, exposure to 0.0001% MO caused <10%
cytotoxicity to all cells. At 24 h, 0.0025 %MO caused maximal cytotoxicity; 0.001% MO caused 10-
70% cytotoxicity. At longer exposure times, epithelial cells were more susceptible to cytotoxic effects
of MO. There was little or no detectable IL-1-stimulated production of IL-6 or IL-8 by cells exposed to

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0.0025% MO, probably reflective of loss of viability. At subtoxic MO levels (0.00001-0.001%), there
was a significant reduction of IL-1-stimulated IL-6 and IL-8 production by fibroblasts, but not by
epithelial cells (Tipton 2003).

The effect of MO on IL-l-stimulated PGE(2) production and NF-B activation in gingival fibroblasts and
epithelial cells was determined. Cells were preincubated with MO, exposed to IL-l, cytoplasmic and
nuclear fractions were isolated, and activated NF-B was measured using an ELISA-based assay. IL-l
increased nuclear activated NF-B levels in fibroblasts and epithelial cells [10-and 2.5-fold over
controls, respectively (p=0.0001)], and these increases were not significantly affected by MO. PGE(2)
was measured in cell supernatants by ELISA, after preincubation with MO and exposure to IL-1. MO
inhibited IL-l-stimulated PGE(2) production by fibroblasts (p=0.001), but not epithelial cells. The data
suggest that gingival epithelial cells and fibroblasts may differ in the magnitude of NF-B activation
after IL-l stimulation, and that MO inhibition of IL-l-stimulated IL-6 production in fibroblasts is due in
part to inhibition of PGE(2), but not NF-B activation (Tipton 2006).

Hypoglycaemic effects
Intragastric treatment of normal and diabetic rats with a 5% w/v aqueous extract of myrrh (extracted
with boiling water then filtered) daily for one week at 10 ml/kg body weight lowered fasting blood
glucose levels in both groups and, in the oral glucose tolerance test, significantly increased glucose
tolerance in both normal (p<0.02) and diabetic animals (p<0.05) (Al-Awadi 1987).

Oral administration of two fractions (200-250 mg/kg body weight) and two pure furanosesquiterpenes
(150-175 mg/kg) from myrrh (C. myrrha) to obese diabetic mice produced significant reductions in
blood glucose at 27 hours post-dose (p<0.005 in all cases). One active fraction at 200 mg/kg reduced
blood glucose by 50% (p<0.0001), compared to a 41% reduction with the oral antidiabetic metformin
at 250 mg/kg (Ubillas 1999).

Antithrombotic activity
Powdered myrrh (C. molmol), administered orally at 100 mg/kg body weight, provided 86% (p<0.05)
protection against ADP/adrelanine-induced thrombosis in mice, comparable to the 94 % (p<0.05) by
acetylsalicylic acid at 20 mg/kg (Olajide 1999).

Antischistosomal activity
In several experimental studies in mice, the antischistosomal activity of a purified extract of myrrh
(Mirazid) has been investigated. Some studies have concluded that the efficacy is promising, whereas
others have been unable to confirm this result (Hassan 2003, Massoud 2004a, Massoud 2004b,
Massoud 2005, Hamed 2005, Botros 2004).

Assessors overall conclusions on pharmacology

Myrrh is a gum-resin with complicated chemistry. Best investigated are the components of the volatile
oil, which are dominated by furano-sesquiterpenes, some of which have pharmacological activity. A
number of pharmacodynamic effects in animal experiments have been described for the resin as well
as for isolated terpenes. Of relevance for the traditional indications gingivitis, stomatitis, wounds and
furuncles are the reported antibacterial, local anaesthetic and anti-inflammatory effects, and possibly,
the antifungal and the analgesic effect. The traditional use involves a direct application of the tincture
to the affected areas in the mouth or on the skin, so there is a reasonable plausibility that the
experimentally observed effects may be clinically relevant.

In Egypt, myrrh is used for treatment of bilharzia and several Egyptian investigations have
demonstrated antischistosomal activity of oral preparations of the herbal substance. This activity could,
however, not be confirmed by other investigators. The potential antischistosomal activity of myrrh
remains controversial.

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3.2. Overview of available pharmacokinetic data regarding the herbal
substance(s), herbal preparation(s) and relevant constituents thereof

No information.

3.3. Overview of available toxicological data regarding the herbal

substance(s)/herbal preparation(s) and constituents thereof

Single dose toxicity

In mice, no visible signs of toxicity and no mortality were observed at oral doses of resin 3 g/kg bw
(Rao 2001).

In rats, the acute oral LD50 value of myrrh oil is reported as 1.65 g/kg bw (1.40 1.90 g/kg) (Opdyke
1976).

Repeat dose toxicity

Myrrh resin was administered to mice via the drinking water at a dose of 100 mg/kg/day during 3
months. No toxic symptoms were observed. The weight gain in the myrrh group was significantly
(p<0.05) higher than in the control group. After treatment the average weight of the vital organs and
conditions of the viscera were normal and comparable to that of the control animals. The weight of
testes, caudae epididymides and seminal vesicles was significantly (p<0.05) higher in the myrrh group
as compared to the control. Biochemical studies showed no significant differences as compared to the
control. Haematological studies revealed a significant (p<0.05) rise of RBC and haemoglobin levels in
the myrrh group as compared to the control (Rao 2001).

Myrrh resin given daily to 6 months-old goat kids (0.25, 1 and 5 g of resin/kg/day) resulted in death
between day 5 and 16 in the doses 1 and 5 g/kg/day. The lowest dose (0.25 g/kg/day) was apparently
not toxic (Omer 1999).

Genotoxicity
Oral administration of a fresh aqueous suspension of myrrh to mice for 7 days at 125 500 mg/kg
bw/day showed no mutagenicity in the micronucleus test. The levels of DNA and protein in hepatic
cells were not affected but there was a significant decrease in their RNA content, comparable to that of
cyclophosphamide (Qureshi 1993).

Myrrh reduced the genotoxicity produced by lead acetate in mice (El-Ashmawy 2006).
In rats, a preparation of myrrh (Mirazid) caused a non-significant increase in the incidence of
chromosomal aberrations at an oral dose of 500 mg/kg bw/day for 6 weeks. This dose had no
hepatotoxic effect (Omar 2005).

Carcinogenicity
No information.

Reproductive and developmental toxicity

No information.

Local tolerance
No irritation, sensitization (in 21 volunteers) or phototoxicity was found for myrrh oil (Opdyke 1976).

In tests of myrrh in the local lymph node assay (LLNA) in mice, a dose-dependent cell proliferation was
observed. The stimulation index (SI) in the radioactive LLNA was more than 3, indicating that myrrh
has a dermal sensitizing potential. Flow cytometric analysis of the B- and T-cell populations in the local
lymph nodes indicated that myrrh is a weak sensitizer (Lv 2009).

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Assessors overall conclusions on toxicology

Preclinical data on the toxicity of Commiphora molmol Engler, gum-resin is incomplete.

Limited genotoxicity tests (micronucleus test in mice) have been performed, which indicated no
genotoxic potential. Due to the antibacterial effect of myrrh, no results from Ames test are to be
expected.

There are no reports on reproductive and developmental toxicity.

There are some reports in the literature about tests of the local tolerance of myrrh. An old report from
1976 in human volunteers indicated no irritating or sensitising effects, whereas a very recent study in
the LLNA indicated a weak sensitising potential. The LLNA is a validated OECD test, and attention
should be given to the sensitizing potential of myrrh.

The analgesic effect following high doses of myrrh and the isolated terpenes furanodesma-1.3-diene
and curzarene on oral administration is noteworthy as it seems to involve an opioid effect. No signals
of abuse of myrrh have, however, been retrieved from the scientific literature.

3.4. Overall conclusions on non-clinical data

Antibacterial, local anaesthetic and anti-inflammatory effects of myrrh extracts and isolated terpenes
have been shown in experimental models. These pharmacological effects make the traditional
medicinal uses of myrrh and myrrh tincture plausible in the indications a) minor ulcers and
inflammation in the mouth (stomatitis and gingivitis) and b) minor wounds and furuncles.
There is also a historical medicinal use of myrrh and myrrh tincture for gastrointestinal disorders. This
use possibly has some support by the experimental data on opioid and cytoprotective effects of myrrh.
The oral use of myrrh (tincture) as single active ingredient seems to have declined during the last
decades (Barnes 2007), and is not included in recent handbooks like Kommission E (Blumenthal, 2000)
and ESCOP (2003).

4. Clinical Data
For all studies cited, it should be stated by means of a detailed description which herbal
substance(s)/herbal preparation(s) have been used and information should be provided for each
preparation separately.

4.1. Clinical Pharmacology

No information available.

4.1.1. Overview of pharmacodynamic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents

See above section 3.

4.1.2. Overview of pharmacokinetic data regarding the herbal

substance(s)/preparation(s) including data on relevant constituents

No information available.

Assessors overall conclusions on clinical pharmacodynamics: No information on clinical

pharmacodynamics is available.

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4.2. Clinical Efficacy

4.2.1. Dose response studies

No information available.

4.2.2. Clinical studies (case studies and clinical trials)

No clinical studies on the efficacy related to the traditional indications are available.

A commercial extract of myrrh Mirazid, marketed for treatment of schistosomiasis, has been subject
to several clinical studies in Egypt but in analogy with the pharmacodynamic studies of this
preparation (see above) the results are controversial. Two open studies, comprising a total of 212
patients, reported an excellent cure rate (92%) of an oral dose of 10 mg/kg/day for 3 days (Sheir
2001, Soliman 2004).
This result could not be confirmed in two other open studies. In one of these (Barakat 2005) Mirazid
was given to 45 patients in a dose of 2 capsules/day for 3 days and the effect compared to a dose of
40 mg/kg of praziquantel given to 38 other patients. The cure rate obtained with Mirazid was 15.6%,
compared to praziquantel (73.7%). Also a second treatment with Mirazid gave a very low cure rate.
In the second study (Botros 2005) a total of 1131 patients (459 school children and 672 household
members) were randomly assigned to two groups. One group was given 300 mg/day of Mirazid for 3
consecutive days and the second received praziquantel at a single dose of 40 mg/kg. Mirazid showed
cure rates of 9.1% and 8.9% in S. mansoni-infected school children and household members,
respectively, compared with cure rates of 62.5% and 79.7% respectively, in those treated with
praziquantel.

Good cure rates were reported in an open study on treatment of human fascioliasis (liver fluke) with
Mirazid (Abo-Madyan 2004).

The effect of myrrh for treatment of the zoonotic disease fascioliasis, caused by Fasciola, a liver fluke
that infects sheep, goats and cattle for which humans act as an accidental host, has been investigated.
7 patients who were passing Fasciola eggs in their stools were treated with a formulation consisting of
8 parts of resin and 3.5 parts of volatile oils, all extracted from myrrh. The dose was 12 mg/kg/day for
6 consecutive days in the morning on an empty stomach. Patients were followed for 3 months. The
therapy proved to be effective, with pronounced improvement of general condition and amelioration of
all symptoms and signs. A dramatic drop in the egg count was detected at the end of treatment. Eggs
were no longer detectable in the faeces 3 weeks after treatment and after a follow-up period of 3
months. High eosinophilic counts, elevated liver enzymes and Fasciola antibody titers returned to
nearly normal. No signs of toxicity or adverse effects were observed (Massoud 2001).

4.2.3. Clinical studies in special populations (e.g. elderly and children)

No information.

4.3. Overall conclusions on clinical pharmacology and efficacy

No studies of clinical efficacy related to the traditional indications are available.

There is no doubt that myrrh has a long-standing use. As mentioned in the introduction, myrrh was
used as a medicine as far back as the ancient Greeks and Romans. Particularly the use in treatment of
wounds and mouth infections is documented in the classical times. Myrrh and myrrh tincture have then
been included and remained in many pharmacopoeias over the centuries and is still included in the
most recent edition of Ph. Eur. On the basis of long-standing use and experience, the efficacy of myrrh

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must be seen as plausible in the traditional indications a) minor ulcers and inflammation in the mouth
(stomatitis and gingivitis) and b) minor wounds and furuncles.

The results on antischistosomal effect and effect on liver fluke infection are controversial and require
further studies before any firm conclusions can be made. There are no signals that myrrh has had a
systematic use in these indications within the European Union.

5. Clinical Safety/Pharmacovigilance
Myrrh is listed by the Council of Europe as a natural source of favouring and may be added to
foodstuffs in small quantities (Barnes 2007).

Myrrh and the essential oil have been evaluated by the Committee of Experts on Cosmetic Products of
the Council of Europe and have been classified into Category A Plants and plant preparations that can
be used in cosmetic products. Myrrh and the essential oil have cosmetic uses in e.g. toothpastes,
mouthwashes and in fragrances (Council of Europe 2001).

5.1. Overview of toxicological/safety data from clinical trials in humans

No information available.

5.2. Patient exposure

No information available.

5.3. Adverse events and serious adverse events and deaths

Allergic contact dermatitis caused by the Chinese orthopaedic solution tieh ta yao gin was
demonstrated to be due to the content of myrrh and mastic (Lee 1993a, 1993b).

Two cases of contact dermatitis due to plasters containing myrrh for treatment of wrist tendonitis have
been reported (Gallo 1999).

Strong allergy to myrrh solution and myrrh powder, resulting from application of the products for
wound healing, is reported (Al-Suwaidan 1998).

5.4. Laboratory findings

No information available.

5.5. Safety in special populations and situations

Drug interactions: A case of interaction with warfarin has been reported. The anticoagulant effect of
warfarin was reduced after the patient had taken an aqueous extract of boiled roots of Commiphora
molmol as a treatment for bronchitis (Al Faraj 2005).

Assessors comment: This report on boiled aqueous root extract of C. molmol is of limited relevance for
the use of myrrh resin (tincture).

5.6. Overall conclusions on clinical safety

Very little clinical safety information is available. Apparently, there is a widespread cosmetic use of
myrr and the essential oil, and the Council of Europe has approved this use. Nevertheless, there are a
few reports on allergic skin reactions in the literature, and this is mentioned in the monograph.

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6. Overall conclusions
Sufficient data have not been retrieved from the literature to support any well-established medicinal
use.

Myrrh and its tincture have a very long history and tradition of medicinal use. The required 30 years of
medicinal use (including 15 years within the European Union) must be considered fulfilled.

The main areas of traditional medicinal use of myrrh and myrrh tincture have been treatment of
infections/inflammation and pain in the mouth, infected wounds and other skin infections, and as a
remedy for various gastrointestinal disorders.

The oral use for gastrointestinal disorders appears to have declined very much in the last 30 years and
does not seem to be common practice today according to several authoritative handbooks of recent
dates. The uses that still exist today appear to be limited to myrrh tincture as an ingredient in multi-
component recipes. It is not recommended to include myrrh tincture for oral use in the Community
herbal monograph.

The oromucosal use of myrrh tincture for oral infections/inflammations is currently in practice. For
safety reasons it appears reasonable to limit the use in self medication to the indications minor ulcers
and inflammation in the mouth, such as stomatitis and gingivitis. These conditions are normally
expected to benefit from an improved oral hygiene and the experimentally shown antibacterial, local
anaesthetic and anti-inflammatory activity of myrrh tincture may contribute to that. The posology
recommended in different handbooks are overall in agreement. It should be noted in the product
information that the use of myrrh tincture as a gargle in gingivitis cannot be used as a substitute for
careful teeth-brushing.

The cutaneous use of myrrh tincture for treatment of infected wounds and skin inflammations has a
long tradition. Again, the experimentally shown antibacterial, local anaesthetic and anti-inflammatory
activity of myrrh tincture makes this use sensible. The content of 90% ethanol in the tincture will most
certainly also contribute to an antimicrobial effect. The alcohol may, however, also cause a
considerable pain when applied to a large wound. This is perhaps also part of the traditional use. For
reasons of safe self medication it appears reasonable to limit the use to minor wounds and small boils
(furuncles). These conditions are normally self limiting in character and normally do not require a
consultation of a physician.

The risks involved in oromucosal and cutaneous use of myrrh tincture are generally estimated to be
low. A few clinical case reports in the literature and results from tests in mice point to a possibility of
allergic skin reactions. Myrrh is, however, acceptable for use in both food and cosmetic products
according to evaluations made by the Council of Europe.

Overall, a monograph on myrrh (tincture) is recommended with the following therapeutic indications:

a) Traditional herbal medicinal product for treatment of minor ulcers and inflammation in the mouth
(stomatitis and gingivitis).

b) Traditional herbal medicinal product for treatment of minor wounds and small boils (furuncles).

with the statement that The product is a traditional herbal medicinal product for use in specified
indications exclusively based upon long-standing use.

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Annex

List of references

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